Effect of CYP3A4 and PPARA polymorphism on concentration-to-dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients.

Objectives: Polymorphism in cytochrome P450 3A4 (CYP3A4) and its regulatory gene peroxisome proliferator activated receptor (PPARA) may significantly affect the metabolism of tacrolimus. This study aims to explore the effect of the single nucleotide polymorphisms (SNP) of cytochrome P450 3A4 and PPARA on the pharmacological variables of adverse effects and the concentration-to-dose ratio (CDR) of the immune suppressant drug tacrolimus in Pakistani liver transplant recipients. Methods: Eighty-one liver transplant patients were included and their demographic and clinical data were recorded. Dosages and trough levels of tacrolimus measured by electrochemiluminescence (ECLIA) were recorded daily. Genotyping for transplant recipients was performed for CYP3A4 rs35599367, PPARA rs4253728 and rs4823613. Incidence of sepsis, acute cellular rejection (ACR) and other adverse effects were recorded. Results: Liver transplant recipients with CYP3A4 rs35599367 CT and TT genotype reported higher tacrolimus CDR compared to the CC genotype during week-1 (p<0.001) and week-2 (p =0.03) post-transplantation period. CYP3A4 rs35599367 polymorphism presented a significant association with nephrotoxicity, sepsis, seizures and psychosis. Significant association of PPARA rs4253728 and PPAARA rs4823613 polymorphism with ACR was observed. Conclusion: Genotyping for CYP3A4 rs35599367 polymorphism during dose titration may shorten the duration to reach optimal tacrolimus trough levels and may help predict adverse events in transplant recipients receiving tacrolimus; genotyping for PPARA rs4253728 and rs4823613 may predict the incidence of ACR.

Influence of ABCB1 gene polymorphism on concentration to dose ratio and adverse effects of tacrolimus in Pakistani liver transplant recipients.

OBJECTIVE: To evaluate the possible association of ABCB1 single nucleotide polymorphism (SNPs) of the ABCB1 gene with tacrolimus dosages, concentration-to-dose ratios (CDR) and adverse effects in Pakistani liver transplant recipients. METHODS: This observational study was conducted at Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad and Basic Medical Sciences Institute, Karachi from September 2016 to July 2020. Eighty-one liver transplant recipients were included. Demographics, clinical data, tacrolimus trough levels and doses were monitored. Electrochemiluminescence immunoassay (ECLIA) was used to measure tacrolimus trough levels. Transplant recipients were genotyped for three ABCB1 SNPs (rs1045642, rs2032582 and rs1128503). Acute cellular rejection (ACR), sepsis and other adverse events were monitored. RESULTS: ABCB1 rs1045642 CC genotype showed lower tacrolimus CDR as compared to CT and TT genotype in the first week of the post-transplantation period (p=0.02). There was a significant association of polymorphisms in rs1045642, rs2032582 and rs1128503 with psychosis, sepsis and ACR respectively. CONCLUSION: Identification of ABCB1 rs1045642 polymorphism may shorten the time to achieve optimum levels of tacrolimus during dose titration. ABCB1 polymorphism rs1045642, rs2032582 and rs1128503 may predict adverse effects in liver transplant recipients receiving tacrolimus.

Clinical efficacy and tolerability of Gabapentinoids with current prescription patterns in patients with Neuropathic pain.

OBJECTIVE: To investigate the current dosing regimens of gabapentinoids in Pakistani patients with neuropathic pain and to compare their clinical efficacy and tolerability in terms of pain relief and adverse effects using difference in pain score as a treatment outcome. METHODS: This observational, prospective study was conducted in 320 patients with neuropathic pain from August 2016 to March 2018 at Basic Medical Sciences Institute (BMSI), Karachi in collaboration with Shifa International Hospital and Benazir Bhutto Hospital, Islamabad. Demographic data, treatment-related adverse effects and pain intensity was documented at recruitment and follow up visits at two, four and eight weeks. Discontinuation due to adverse effects and lack of efficacy were also recorded. Data was entered and analyzed using SPSS version 22. RESULTS: Mean age of patients was 52.57±12.47 and the most common ethnicity were Punjabi speaking population (66%). Diabetic neuropathy (51%) was the most common etiology followed by radicular pain (25%). Mean dosages of pregabalin and gabapentin were 114mg and 470mg respectively. Mean pain score was significantly reduced by gabapentinoids (<0.001). Dizziness, drowsiness and somnolence were frequent adverse effects. Common dosages for pregabalin and gabapentin were 75 mg/day and 300 mg/day respectively. CONCLUSION: Current dosing regimens of gabapentinoids in Pakistani patients with neuropathic pain were found to be efficacious at low dosages in comparison to international recommended dosages. Gabapentin and pregabalin were both similar in terms of reducing pain score but onset of pain relief was relatively faster with pregabalin. Dizziness, drowsiness and somnolence were frequently reported with both gabapentinoids; however, visual blurring, ataxia and weight gain were observed only with the use of pregabalin. Adverse effects are frequently observed with gabapentinoids which necessitates reverting back to low dosages or switching to other drugs for pain relief.

Atorvastatin as an adjuvant with betamethasone valerate reduces disease severity and cardiovascular risks in Psoriasis.

OBJECTIVES: To evaluate the effect of Atorvastatin as an adjuvant with betamethasone valerate on disease severity and cardiovascular risks in chronic plaque type psoriatic patients. METHODS: It is an interventional study conducted in Pharmacology Department of BMSI, JPMC with the collaboration of Dermatology Department of JPMC, Karachi. The duration of study was from June 2013 to June 2016. Seventy five psoriatic patients were prescribed Tablet Atorvastatin 40-20 mg/day (40mg for first three months twice daily followed by 20mg once daily for the next three month) plus topical Betamethasone Valerate 0.1% once daily for 6 months (three week apply than one week interval). The efficacy and safety profile of drugs was measured by PASI, DLQI, hsCRP, LFTS and Lipid profile. RESULTS: The percentage change of PASI is 86.749±0.547, DLQI is 82.697±.2.61 and hsCRP is 40.371±8.505, which showed highly significant improvement in patient at the end of last follow up. LFTs and CPK for safety profile of therapy showed non-significant results. CONCLUSION: Atorvastatin used as an adjuvant therapy with currently existing standard therapy (topical betamethasone) in patients having mild to moderate plaque type psoriasis reduces disease severity and cardiovascular risks.

The hepatoprotective role of Silymarin in isoniazid induced liver damage of rabbits.

OBJECTIVE: To evaluate the hepatoprotective role of Silymarin against isonicotinylhydrazine-induced hepatotoxicity in rabbit model. METHODS: The experimental animal study was held at Jinnah Postgraduate Medical Centre, Karachi, from April to September 2013 and comprised rabbits weighing 1-1.5kgof either gender. The animals were divided randomly into equal groups: group I underwent liver function test without any drug; in group II effects of Silymarin (50mg/kg/day orally) was observed; in group III isoniazid (50mg/kg/dayorally) was administered; and in group IV combined effects of isoniazid and silymarin were observed. Liver function tests were performed at day0 and after the treatment at day19. SPSS 16 was used for statistical analysis. RESULTS: The 28 rabbits in the study were divided in four groups of 7(25%) each. No mortality was recorded in any group. In group III, bilirubin level was increased and alanine transaminase was decreased significantly (p<0.05 each). In group IV, there was significant improvement in serum billirubin and serum alanine transaminase (p<0.05 each). CONCLUSIONS: Isonicotinylhydrazine-induced hepatotoxicity was well treated by concurrent administration of Silymarin.

Comparison of efficacy and safety of topiramate with gabapentin in migraine prophylaxis: randomized open label control trial.

OBJECTIVE: To compare the efficacy and safety of topiramate with gabapentin in the prophylaxis of migraine patients. METHODS: A 12-week randomised open label control trial was conducted at the Department of Pharmacology and Therapeutics, Basic Medical Sciences Institute, Jinnah Postgraduate Medical Centre (JPMC), Karachi from January to March 2011 involving 80 outpatients who had a history of migraine. The sample was divided into two equal groups. Primary efficacy measure was changed into mean monthly migraine frequency. Secondary efficacy measure included reduction in severity and average duration of an attack. Chi square test and paired t-test were used to analyse the data through SPSS 15. RESULT: Reduction in mean monthly migraine frequency (10.67 +/- 4.25 to 1.82 +/- 2.02) in the topiramate group was significantly greater compared with (11.97 +/- 4.452 to 2.73 +/- 2.59) that in the gabapentin group (p < 0.001). Reduction in severity from 6.60 +/- 2.122 to 1.03 +/- 0.92 in the topiramate group was also significantly greater compared with 6.93 +/- 1.90 to 1.18 +/- 1.01 in the gabapentin group (p < 0.001). Reduction in the average duration of attacks from 25.77 +/- 22.32 hours to 1.05 +/- 1.06 hours in the topiramate group was significantly greater compared with 22.20 +/- 20.72 to 1.08 +/- 1.40 hours in the gabapentin group (p < 0.001). Weight loss and numbness were common adverse effects in the topiramate group. Dizziness, weight gain and somnolence were reported in the gabapentin group. CONCLUSION: Gabapentin appeared well tolerated in 30 (75%) patients compared to topiramate in 23(57.5%) patients. Both drugs were equally effective in migraine prophylaxis.

Lack of impact of OCTN1 gene polymorphisms on clinical outcomes of gabapentinoids in Pakistani patients with neuropathic pain.

BACKGROUND AND OBJECTIVE: Gabapentinoids are the first-line drugs for neuropathic pain. These drugs are the substrate of organic cation transporter (OCTN1) for renal excretion and absorption across the intestinal epithelium. Gabapentinoids exhibit wide interindividual variability in daily dosage and therapeutic efficacy which makes titration regimens prolonged for optimal efficacy. The present study aimed to investigate the possible influence of the single nucleotide polymorphism (SNP) of OCTN1 on therapeutic efficacy and safety of gabapentinoids in neuropathic pain patients of the Pakistani population. METHODS: Four hundred and twenty-six patients were enrolled in the study. All participants were genotyped for OCTN1 rs1050152 and rs3792876 by PCR-RFLP method and followed up for eight weeks. The therapeutic outcomes of gabapentinoids, reduction in pain score, inadequate or complete lack of response, adverse events (AEs) in responders and discontinuation of treatment on account of AEs were recorded for all patients. RESULTS: There was no significant association of genotypes and alleles of both SNPs on the clinical response of gabapentinoids (P ˃ 0.05). Similarly, significant differences were not found in the reduction of pain scores and AEs among different genotypes in the responders. The present study has reported the association of OCTN1 rs1050152 and rs3792876 polymorphisms with clinical outcomes of gabapentinoids for the first time in the real-world clinical setting. CONCLUSION: Our results suggest a lack of influence of OCTN1 genetic variants in the determination of clinical response to gabapentinoids in patients with neuropathic pain in the Pakistani population. These findings signify the role of renal functions in predicting the interindividual variability to therapeutic responsiveness of gabapentinoids.

Safety and efficacy of lodoxamide in vernal keratoconjunctivitis.

OBJECTIVE: To observe the safety and efficacy of topical Lodoxamide eye drops in patients with diagnosed vernal keratoconjunctivitis (VKC). METHODS: This study was conducted at Department of Pharmacology and Therapeutics, BMSI, JPMC, Karachi in collaboration with Department of Ophthalmology, JPMC, Karachi, from April to October, 2009. A total of forty patients with diagnosed vernal keratoconjunctivitis were selected and enrolled consecutively from the out patient department (OPD) of Ophthalmology. Each patient received two drops of Lodoxamide eye drops topically in each eye four times daily. Patients were examined with a torch and slit lamp at baseline and follow-up visits. RESULTS: Out of 40 patients included, 39 completed the study and there was a significant effect of the drug on symptoms and signs of the disease. At the end of the study, 38 (97.4%) were cured, with few side effects. The cure criteria was based on patient's history of becoming symptom-free and resolution of ocular signs. CONCLUSION: Topical lodoxamide eye drops, when used for treatment of VKC, are effective with fewer adverse effects.

To study the efficacy of Losartan on urinary uric acid excretion in Thiazide induced hyperuricemic and hypertensive patients.

The precise relationship of Hyperuricemia found in hypertensive patients is still obscure; this study is a urinary uric acid lowering intervention with Losartan in hypertensive patients induced by Thiazide diuretics. A number of pharmacological agents like loop diuretics, similarly low doses of aspirin (<3g daily) aggravate Hyperuricemia. The effect of Losartan on urinary uric acid excretion In Hypertensive patients with Thiazide induced Hyperuricemia were investigated in the Department of pharmacology and therapeutics, Basic Medical Sciences Institute Jinnah Postgraduate Medical Centre Karachi. It was randomized, open label, prospective, comparative study. Total 60 hypertensive Hyperuricemic patients were enrolled one by one in this study, selected from medical OPD and wards of Jinnah Postgraduate Medical Centre, Karachi. Patients were divided in three groups. Group-1 patients were treated with Thiazide 50 mg/day, Group-2 with Losartan + Thiazide 50 mg/day, and Group-3 with Losartan 50 mg/day. The effect on urinary uric acid level was measured, after every fortnightly. Treatment with Thiazide + Losartan group and Losartan group showed significantly increase in urinary uric acid excretion. Whereas, Thiazide group decrease in urinary uric acid level. In contrast to Thiazide and Losartan alone Thiazide + Losartan led to a greater increased in urinary uric acid excretion. The average percentage increase in urinary uric acid excretion in Thiazide + Losartan group was -13.27% and the average percentage increased in urinary uric acid excretion was 6.7% in Losartan group. Thus it can be concluded from the present study that urinary uric acid excretion was more increased in combination therapies. Ultimately Losartan decrease serum uric acid level and uricosuric effect of Losartan might be particularly useful in Hyperuricemic patients those on Thiazide diuretic (for hypertension and heart failure).

Influence of single nucleotide polymorphism of LAT1 on therapeutic response to gabapentinoids in Pakistani patients with neuropathic pain.

Gabapentinoids are substrate of L-type amino acid transporter 1 (LAT1) for distribution across the blood-brain barrier. The present study aimed to evaluate the effect of LAT1 rs4240803 genetic polymorphism on the clinical efficacy and tolerability of gabapentinoids in Pakistani patients with neuropathic pain. Three-hundred and ninety-two patients were recruited, genotyped for SNP rs4240803, and followed up for eight weeks to evaluate the clinical response to gabapentinoids in terms of pain relief, inadequate response, and the emergence of adverse events. LAT1 rs4240803 GG, GA, and AA genotype frequency were 33.42%, 47.96% and 18.62%, respectively. Out of 392 patients, 323 responded to the treatment and 17.6% discontinued either due to insufficient response or intolerable adverse events (AEs). GA genotype was more frequent in non-responder group (P Ë‚ 0.001). Maximum pain responders (≥50%) in combination with the lowest incidence of AEs were observed in the GG group, whereas partial responders belonged to GA genotype and with the highest frequency of somnolence (83.6%) and dizziness (69.9%). Overall, 72.5% patients with GA genotype experienced AEs (P Ë‚ 0.001). In conclusion, clinical outcomes of gabapentinoids are influenced by LAT1 rs4240803 polymorphism and population pharmacogenetics should be considered to evaluate the maximum potential of gabapentinoids in the management of neuropathic pain.

Assessment of efficacy and adverse effects of trazodone in the treatment of major depressive disorder.

BACKGROUND: Major depressive disorder is a serious and disabling illness in the world and is common chronic and recurrent disorder. It is the fourth most important cause of worldwide loss in disability. METHODS: This was prospective and open-label study, study conducted in JPMC. Karachi, to evaluate the efficacy and adverse effects in major depressive disorder individuals. A total of 40 patients irrespective of the gender, aged 18 years up to 65 years were enrolled from OPD of Psychiatry Department. Follow-up visits were carried out fortnightly after making evaluation of symptoms at baseline visit (day 0), follow-up continued till 90 days when the results were compiled. RESULTS: Statistically significant (p < 0.05) results were observed in all the parameters at the end of study, i.e., day 90. CONCLUSION: Among all the symptoms of major depressive disorder, trazodone proved to be more effective in controlling insomnia.

Gauging the Positive Predictive Value of Exercise Tolerance Test Using Angiographic Evaluation: A Cross-Sectional Analysis From a Developing Country.

Background Exercise tolerance test (ETT) and angiographic evaluation are important tools to evaluate patients presenting with ischemic cardiac pathologies. Angiographic evaluation is regarded as the gold standard diagnostic modality to diagnose coronary artery disease (CAD). Our study aims to evaluate the positive predictive value (PPV) of ETT to diagnose CAD using coronary angiography. Methods We conducted a cross-sectional study that analyzed 94 patients with a positive ETT test after the application of strict inclusion and exclusion criteria. All 94 patients were referred for angiography after a positive ETT test. Data collection was performed using a structured proforma, and analysis was carried out on Statistical Package for Social Sciences (SPSS) version 23 (IBM Corp., Armonk, NY). PPV for various demographic characteristics was calculated. Results Out of 94 patients, 76 were males and 18 were females with a mean age of 52.28 ± 7.55 years. A total of 35.1% of the patients had type-2 diabetes, and 31.9% were hypertensive. On coronary angiography, only 25 patients had normal findings, and 69 patients had a significant occlusion in at least one of the major coronary arteries. The overall PPV of the ETT against angiographic evaluation was 73.40%. The PPV for females, hypertensives, non-smokers, and non-diabetics was lower than the PPV of males, smokers, non-hypertensives, and diabetics. Conclusion Angiographic evaluation of patients with positive ETT findings has a high likelihood of false positivity especially among females, non-smokers, hypertensives, and non-diabetics. The results of ETT must be interpreted with caution in these subsets of the population. Invasive radiological modalities can be used for diagnosis; however, such modalities do not elucidate the functioning of myocardium under stress.

Influence of sibutramine, orlistat and Ispaghula in reducing body weight and total body fat content in obese individuals.

BACKGROUND: The correlations between combined body fat parameters and risk factors of obesity explained a portion of the variation in the weight, BMI and waist circumference, the average number of categorical metabolic risk factors increases progressively with increasing total body fat content. There is currently no data available in which influence of drugs can be assessed on total body fat content. This was a non-randomized, prospective, open-label, parallel group study was conducted to compare the effectiveness of sibutramine, orlistat and ispahgula in reducing body weight and percentage of total body fat content in obese individuals. METHODS: A nonrandomized, open label, prospective, intention to treat clinical trial was conducted from July 2008 to March 2009 in JPMC, Karachi, Pakistan. The study was based on three arms A (ispahgula), B (orlistat) and C (sibutramine) comprising 40 patients in each. The selection criteria has included patients from either sex with age 18 years or more with BMI > or =30 as obese with or without associated risk factors and BMI > or = 27 < 30 as over weight only if any significant risk factor is present. Compliance on diet chart and instruction for life style modification were assessed monthly. RESULTS: The comparison of mean difference in percentage of total body fat content between the groups and within the groups at day 150 is (p-value) 0.029 and difference in body weight is (p-value) 0.042 which is statistically significant. CONCLUSION: Sibutramine is more effective than ispahgula and orlistat in reducing body weight and percentage of total body fat content in obese patients.

Clinical Efficacy and Safety of Tacrolimus in Pakistani Living Donor Liver Transplant Recipients.

OBJECTIVE: To evaluate the association between tacrolimus trough levels and dosage in Pakistani patients undergoing live donor liver transplantation (LDLT), and the efficacy and adverse effects at different tacrolimus trough levels and dosages. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Shifa Tameer-e-Millat University, Islamabad and Basic Medical Sciences Institute, Karachi, from September 2016 to October 2018. METHODOLOGY: Sixty liver transplant recipients were included. Demographics, clinical data, tacrolimus trough levels and doses were monitored as per routine protocol. Electrochemiluminescence immunoassay (ECLIA) was used to measure tacrolimus trough levels. Acute cellular rejection (ACR), sepsis and other adverse events were monitored at different tacrolimus trough levels in early post-transplantation period. RESULTS: Mean age of transplant recipients was 49.1 ± 10.6 years. Mean tacrolimus trough levels were 6.1 ± 2.2 ng/ml and mean dose was 0.94 ± 0.3 mg. Sepsis (27%) psychosis (20%), seizures (10%), and renal insufficiency (13%) were the most common adverse effects. Acute cellular rejection (ACR) was observed in 15% patients. Patients with sepsis had significantly high mean tacrolimus levels of 7.7 ± 2.5 ng/ml versus 5.5 ± 1.9 ng/ml (p=0.001). Mean tacrolimus trough levels in patients with ACR were significantly lower (4.05 ± 1.6 ng/ml vs. 6.43 ± 2.2ng/ml, p=0.003). None of the patients with a single tacrolimus trough level >10 ng/ml experienced ACR. CONCLUSION: A tacrolimus trough level between 5 to 7.5 ng/ml appears to be safe in Pakistani liver transplant recipients significantly minimising the risk of ACR and other adverse events.

Comparison of Bioelectrical Impedance and Navy Seal Formula to Measure Body Composition in Medical Students.

Objectives There are many different ways to measure body composition and bioelectric impedance is one of the most popular methods to measure body ratios. The navy-seal formula is another simple way of measuring body fat ratio which takes into account simple variables such as gender, weight, height, waist, hip and neck circumference. The objective of our study was to compare the results of body fat composition by these two methods. Materials and methods Height and weight were measured in 85 study participants using a wall-mounted stadiometer and digital scale. Body composition measurements were recorded using a simple measuring tape. Participants were then asked to stand on the electrical impedance machine to determine the body fat and muscle mass. Data were analyzed on IBM's statistical package for the social sciences (SPSS) version 23 (IBM, Armonk, NY). Results The Navy-seal formula had slightly higher values for both muscle mass and body fat ratio in both genders and across all body mass index (BMI) categories. Body fat ratio and muscle mass of both genders were similar in underweight, normal, over weight and obese participants. In males, the results on two instruments showed more similarity with the increase in BMI, whereas, in females, the results of the two methods were more similar in the normal weight category. Conclusion Navy-seal formula and bioelectrical impedance are both simple and reliable instruments to measure body composition in adults. The navy-seal formula can be used to screen individuals with high-fat body fat ratio whereas bioelectric impedance can be used to measure the body composition for personal monitoring.